The government has rights in this invention by virtue of grants from the Public Health Service and the National Institute of Allergy and Infectious Diseases.
This application is in the field of synthetic organic chemistry and specifically relates to an improved method of synthesis of 2',3'-dideoxynucleosides.
A nucleoside is a molecule consisting of a 5-carbon sugar and a purine or pyrimidine base. Addition of a phosphate group to the 5' position of the nucleoside converts it into a nucleotide. Nucleotides are the building blocks for the nucleic acids, RNA (ribonucleic acid) and DNA (deoxyribonucleic acid).
Several nucleosides have recently shown antiviral activity against human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2, generally referred to herein as HIV). These two viruses are believed to cause AIDS, or acquired immunodeficiency syndrome.
AIDS is characterized by an imbalance in two basic types of immune system cells, helper/inducer T lymphocytes and suppressor T lymphocytes, with the ratio of suppressor cells to helper/inducer cells greatly elevated. Helper/inducer T cells, defined by a surface antigen called CD4, are responsible for the induction of most of the functions of the human immune system, including the humoral immune response involving the production of antibodies by B lymphocytes and the cell-mediated response involving stimulation of cytotoxic T cells. A condition associated with HIV is AIDS-related complex, or ARC. Most patients suffering from ARC eventually develop AIDS.
AIDS patients who succumb to opportunistic infections, and approximately half of all patients with Kaposi's sarcoma, die within two years of diagnosis. Attempts at reviving the immune systems in patients with AIDS have been unsuccessful.
Among the nucleosides shown to have antiviral activity, including anti-HIV activity, are 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideooxyadenosine (DDA), 2',3'-dideoxyinosine (DDI), 3'-azido-2',3'-dideoxyuridine (CS-87), 2',3'-dideoxy-2',3'-didehydrocytidine (D4C), 3'-deoxy-2',3'-didehydrothymidine (D4T) and 3'-azido-5-ethyl-2',3'-dideoxyuridine (CS-85).
3'-Azido-3'-deoxythymidine (AZT) has been found to be both an unusually potent antiviral agent against HIV-1 in vitro, as reported by H. Mitsuya, et al. Nature, 325, 773, (1987); R. Yarchoan, et al. New Engl. J. Med., 316, 557, (1987); H. Mitsuya, et al. "Modern Concepts and Therapeutic Challenges" AIDS, p. 303 (Marcel Dekker, New York, 1987); H. Mitsuya, et al. Proc. Nat'l Acad. Sci., USA, 82 7096 (1985); and P. A. Furman, et al. Proc. Nat'l. Acad. Sci., USA, 83, 8333, (1986), and to decrease the mortality and opportunistic infections in patients with AIDS. Currently, AZT is the only chemotherapeutic agent available for AIDS patients. AZT was originally synthesized from thymidine as described by J. P. Horowitz, et al., in J. Org. Chem., 29, 2076 (1984). It is currently produced from thymidine for pharmaceutical distribution. Unfortunately, supplies of AZT are now limited and expensive because of the high demand for thymidine, which is obtained from herring sperm.
Recently, a total synthesis of AZT by the condensation of thymine with a preformed 3'-azido-2'-deoxyribofuranose was reported by N. B. Dyatkina, et al., Soviet J. Biorg. Chem., 12, 563 (1986); and G. W. J. Fleet, et al., Tetrahedron, 44, 625 (1988). However, in these methods, the intermediate azido sugar was prepared from D-xylose via the intermediate 1,2:3,5-di-O-isopropylidene-D-xylofuranose or methyl 3,5-O-isopropylidene-D-xylofuranose through a complex, multistep process.
3'-Azido-2',3'-dideoxyuridine (AZDU, CS-87) has also been found to be a potent antiviral agent against HIV-1 in vitro, as reported by R. F. Schinazi, et al., J. Cell Biochem. Suppl. 11D, 74, (1987); R. F. Schinazi, et al., 2nd International Conference on Antiviral Research, Williamsburg, Va., April 100-14, 1988; Antiviral Research, 9, 84, (1988), and is presently undergoing preclinical toxicology studies. AZDU (CS-87) has been synthesized from 2'-deoxyuridine in an approach similar to the synthesis of AZT from thymidine developed by Horowitz, as described by T. S. Lin, et al. in J. Med. Chem., 26, 544 (1983); C. K. Chu, et al., J. Med. Chem. in press. This synthetic route is likewise expensive due to the cost of the starting material for 2'-deoxyuridine.
There is a great need to develop a general synthetic scheme for 2',3'-dideoxynucleosides which is efficient, inexpensive, and based on a readily available starting material. It is essential that those suffering from AIDS be provided effective antiviral drugs at an affordable cost. In addition, an efficient, general synthetic route to these nucleosides will generate new derivatives for research.
It is therefore an object of the present invention to provide a general synthetic route to 2',3'-dideoxynucleosides.
It is a further object of the present invention to provide a synthetic route to 2',3'-dideoxynucleosides which is based on a readily available starting material.
It is a still further object of this invention to provide a synthetic route to 2',3'-dideoxynucleosides which is efficient and inexpensive.
It is another object of this invention to provide an efficient, inexpensive method of preparation of AZT and AZDU which is amenable to large scale production.